Parkinson's disease is characterized by selective loss of dopaminergic neurons in the substantia nigra and a corresponding decrease of dopamine in the target striatum. The extent of motor dysfunction correlates well with the degree of dopaminergic loss. The strategy of replacing the missing neurotransmitter dopamine by systemic administration of the precursor, L-DOPA, or of other direct dopamine agonists has worked surprisingly well in attenuating many of the motor symptoms.
Long-term treatment of Parkinson's disease with L-DOPA is, however, unfortunately complicated by erratic responses (wearing-off's and on-off's), dyskinetic movements, and psychosis. Some of those problems can be controlled by continuous delivery of dopamine agonists using duodenal or intravenous infusions but this is not realistic for long-term therapy. Moreover, this type of systemic delivery cannot avoid stimulation of the dopaminergic system in other areas without development of untoward symptoms such as psychosis. A means for continually delivering dopamine localized to the target area of the striatum may serve to alleviate and prevent many of the long-term complications of the presently available pharmacological treatments.
The most successful dopaminergic transplant in the central nervous system (CNS) has been achieved by use of fetal mesencephalic neurons in rat models of Parkinson's disease. These successes have led to clinical trials of fetal tissue transplants in patients with Parkinson's disease. A limited number of clinical trials have been performed, but the results are not yet clear. Because there are ethical, political, and practical considerations when using human fetal tissue donors, use of cell cultures and autologous donor tissues have also begun to be explored. The adrenal medulla produces catecholamines and can be obtained as autografts; however, the survival of adrenal medullary chromaffin cells has been uniformly poor both in experimental animals and in human patients. This observation has prompted additional plans, such as co-grafting of peripheral nerves as a source of nerve growth factor with the hope that this will enhance survival of the adrenal medulla grafts.
One of the more promising and potentially versatile approaches to the transplant problem is the use of transplants of genetically modified primary cells. Use of primary cultures of cells obtained from a biopsy of the host or of syngeneic subjects minimizes immunological responses of the host to the graft. The methods of primary cell culture and gene transfer have been well established in skin fibroblast systems. The long-term survival of primary skin fibroblast cells after grafting into the CNS has been well documented by light microscopic and ultrastructural studies. This system, then, serves as a biological delivery pump for neurotransmitters and other small molecules such as neurotrophic factors. The utility of the system is two fold: first, it provides a potential therapeutic modality for continuous and localized delivery of neurotransmitters and other biologically active molecules; second, this approach provides an ideal experimental system in which the role of a particular neurotransmitter or neurotrophic factor can be studied in vivo since the only difference between the experimental group and the control group is the presence of a single gene transduced into the primary cells.